Estimating the extent of subclinical arteriosclerosis of persons with prediabetes and diabetes mellitus among Japanese urban workers and their families: a cross-sectional study

One of the most serious complications among person with diabetes is the deterioration of arterial system or the acceleration of arteriosclerosis which could not be easily measured in the past. One method to quantitatively estimate the extent of arteriosclerosis is the use of the pulse wave velocity (PWV). The idea on the association of PWV with arteriosclerosis is traced back to an experiment using artificial blood vessels conducted by Moens in 1878 [1]. Then, Bramwell and colleagues showed that PWV depends on the modulus of arterial volume elasticity by experiments in 1922-23 [1–5]. Their experimental results have been a basis for the development of the measurement device PWV-200 (Fukuda-Denshi Co., Tokyo) which measures PWV propagating through the aorta (thorax, abdomen, and part of common iliac artery) from the aortic valve to the femoral pulsation point, as described by Hasegawa in 1970 [6]. Because PWV is highly correlated with diastolic blood pressure, Hasegawa developed a nomogram showing the association between diastolic blood pressure and PWV. He proposed an adjustment to any measured PWV values at 80 mmHg. As a result, such an adjustment was built into the PWV-200 machine. This is an important step allowing clinicians and researchers to compare PWV values between individuals and between populations. Namekata et al. conducted cardiovascular disease prevention screening in Seattle and found that PWV was positively and significantly associated with aging (≥60 years of age), hypertension, diabetes, the ratio of total cholesterol to high density lipoprotein cholesterol, ex-smokers and negatively and significantly with alcohol consumption among Japanese Americans [7]. In addition, they had similar findings among Japanese urban workers [8].

To overcome some technical difficulty for measuring PWV, the cardio-ankle vascular index (CAVI) was developed as a new indicator of arteriosclerosis in 2004 [9]. CAVI scores quantitatively reflect arteriosclerosis of the aorta, femoral and tibial arteries based on Bramwell-Hill’s equation [1] and stiffness parameter [10] which is allowed to be converted from PWV propagating from the aortic valve to ankle. Some researchers proposed to use CAVI scores as an indicator of atherosclerosis. Nakamura et al. found a strong association of CAVI with the presence of severity of coronary atherosclerosis based on their ordinal logistic regression analysis [11]. Kadota et al. suggested the use of CAVI as a screening tool for atherosclerosis based on their findings from the general population study of 1,014 adults showing strong significant associations of CAVI scores with carotid intima-media thickness and with homocysteine after adjustment for age and sex [12]. Thus, it is considered that CAVI scores reflect arterial stiffness, atherosclerosis and arteriosclerosis of which conditions are overlapping and inseparable. We use CAVI scores to represent the extent of subclinical arteriosclerosis in this paper but it is inclusive of arterial stiffness and atherosclerosis.

To practically use CAVI as a diagnostic tool for determining the extent of arteriosclerosis, our previous study established the baseline CAVI scores by age and gender among cardiovascular disease (CVD) risk-free persons [13]. In our present study we measured CAVI scores and identified persons with abnormally high CAVI scores in Japanese urban workers and their families based on the criteria developed by our studies [13, 14], and then examined the extent of subclinical arteriosclerosis among persons with prediabetes and among persons with diabetes mellitus after making adjustment for major cardiovascular disease (CVD) risk factors.

Characteristics of study participants by age and gender were described in our previous paper [14]. We briefly summarize those here. It is observed that the averages for both systolic and diastolic blood pressure and CAVI scores linearly increased as ages advanced in both genders with an exception of men’s diastolic blood pressure after 60 years of age of which averages slightly decreased. Almost all averages of clinical indicators increased until 60 years of age except HDL-C of which averages were at the same level in both genders. Striking differences in averages of clinical indicators between genders are observed and are unfavorable for men in terms of cardiovascular disease risk. BMI averages ranged from 22.3 to 24.2 among men and from 20.4 to 22.9 among women. Greater prevalence of drinkers and smokers was observed in men than in women. Prevalence of drinkers and smokers was greater in younger women than in older women.

In the present cross-sectional study of Japanese urban workers and their families, prevalence of abnormally high CAVI scores were dose-dependently elevated along with the advancing degree of diabetic status both in men and in women. Compared with normal persons, significantly elevated odds ratios of abnormally high CAVI scores were observed not only in persons with diabetes but also in those with prediabetes.

With regard to the validity to use CAVI scores as an indicator of arteriosclerosis, Otsuka examined 72 deceased patients’ antemortem PWV (which is a basis for deriving CAVI scores) and pathological changes measured by the diffuse fibrotic thickening, formation of atheroma and calcification in the wall of their aorta. He reported multiple regression coefficient R = 0.810 between PWV and scores of those pathological changes [17]. In addition, other researchers reported that CAVI scores were significantly associated with coronary atherosclerosis [11], with carotid intima-media thickness and with homocysteine [12]. Thus, the use of CAVI scores derived from PWV values is valid to estimate the extent of arteriosclerosis.

VaSera VS-1000, which was used in our study, was designed to measure CAVI scores independent of blood pressure at the time of CAVI score measurement and CAVI scores represent the extent of arteriosclerosis between the aortic valve and the ankle. We have shown biological aging of the major artery by measuring CAVI scores in the CVD risk-free group and disease-related pathological aging of the major artery in the CVD high-risk group [13]. CAVI scores allow us to evaluate the extent of arteriosclerosis in the major arteries between the aortic valve and the ankle, to screen persons with subclinical stage of CVD, and provide an opportunity to modify diet and lifestyle to improve CAVI scores as reported by Satoh et al [18]. Thus, the use of CAVI scores potentially leads to savings on high treatment costs and to prolonging many productive lives.

Namekata et al. showed significant odds ratios of the abnormally high aortic pulse wave velocity (PWV, an indicator of arteriosclerosis reflecting stiffness of artery and atherosclerosis) in an association with diabetes among Japanese Americans and among native Japanese (3.66 and 2.43, respectively) [8]. Namekata et al. observed that odds ratios of abnormally high CAVI scores in an association with diabetes after making adjustment for ages were 10.02 for men and 8.42 for women, compared with those who did not have diabetes [14]. In our recent study significant ORs of prediabetes and diabetes were observed in association with most CVD risk factors including age, hypertension, triglycerides ≥ 200 mg/dl and BMI ≥ 25 in both genders [19]. Our results imply much faster advancement of arteriosclerosis among persons both with prediabetes and with diabetes than in the normal persons.

In our present study it is shown that prevalence of abnormally high CAVI scores has an increasing trend with an age increase in all three groups of non-diabetes normal persons, prediabetes and diabetes (Table 2). Our results show that comparing with persons with normal CAVI scores, estimated risks of abnormally high CAVI scores in association with prediabetes and with diabetes were 1.29 times higher and 2.41 times higher, respectively, in men and were 1.14 times higher and 2.52 times higher, respectively, among women (Table 3). Our study results have confirmed the association between prediabetes and arteriosclerosis and the much stronger association between diabetes and arteriosclerosis estimated by CAVI scores.

A limitation of this study is that it is an observational and cross-sectional study. Thus, we cannot tell how many persons with prediabetes will develop diabetes or will return to normal in their blood glucose levels or/and HbA1c levels. The strengths of this study are having the large sample size and being able to adjust for many CVD risk factors with enough statistical power to examine the association of CAVI scores with prediabetes and diabetes mellitus.

In conclusion, both prediabetes and diabetes mellitus were significantly associated with CAVI scores. It is implied that the extent of arteriosclerosis (including arterial stiffness and atherosclerosis) was moderately enhanced among persons with prediabetes and was further advanced among persons with diabetes. Thus, it is important to introduce earlier interventions for changing lifestyle and diet of persons with prediabetes in order to prevent them from developing diabetes and further advancing arteriosclerosis.